Glycidamides

ABSTRACT

2-Phenylglycidamides such as 3-chloro-2-(2,4-dichlorophenyl) glycidamide, are described. The compounds have utility in the polymer field and also possess useful biological activity.

- United States Patent [191 Field of Search, .L ..424/278 [111 3,726,981 Quick 5] Apr. 10, 1973 [s41 GLYCIDAMIDES [56] References Cited [75] Inventor: Carolyn M. Quick, Manteca, Calif. OTHER PUBLICATIONS [73] Assign: 1 P Y York, Murray et alr, J. Am. Chem. Soc., Vol. 56, No. 12, 22 Filed: 03 8 1971 V December 1934, pp. 2749-2751. [21 Appl- P193 3 Pr ir n'ary Examiner-Jerome D. Goldberg I Related Us. Application Data Attorney-Frank R. La Fontame et a1. [62] Dirrision of Ser. No. 5,109, Jan. 22, 1970, Pat. No. vABSTRACT 2-Phenylglycidamides such as 3-chloro-2-(2,4 dichlorophenyl) glycidamide, are described. The com- 52 us. Cl ..424/27s pounds have utility in the polymer field and also Int. Cl. Sess useful biological activity.

4C laims,NoDrawi ngs GLYCIDAMIDES This application is a division of Ser. No. 5,109, filed Jan. 22, 1970, now [1.8. Pat. No. 3,646,211.

' BACKGROUND OF THE INVENTION While substituted glycidamides have been known for many years, relatively few Z-phenylglycidamides have been reported in the literature. As far as is known only 3-methyl-2-phenylglycidamide and 2,3-diphenyl glycidamide have thus far been reported (Murray et al., J. Am. Chem. Soc., 56, 2749 (1934)).

SUMMARY OF THE INVENTION DESCRIPTION OF THE PREEERRED EMBODIMENTS The novel class of compounds of this invention can be described by the formula I wherein X is hydrogen or halogen, Y is hydrogen, halogen or alkyl of l-4 carbon atoms, Z is halogen, nitro, alkyl of l-4 carbon atoms, trifluoromethyl or alkylsulfonyl of 1-4 carbonatoms, H is 'hydrogenandn is l, 2, or 3, with the provisos that when n is less than 3, each Z may be the same or different and when Yis alkyl, X is hydrogen.

The alkyl moieties may bestraight or branched-chain and include methyl, ethyl, isopropyl, butyl and the like.

The halogens are fluorine, chlorine, bromine and iodine.

Mainly because of availability of the starting materials and ease of synthesis the Z-phenylglycidamides of the following formula form a preferred subclass:

wherein R is chlorine, bromine or hydrogen; R, is

Exemplary compounds within this subclass include: when R is chlorine or bromine;

3-chloro-2-(2-chlorophenyl)glycidamide, 3,3-dichloro-2-(2,3-dichlorophenyl)glycidamide, 3-bromo-2(2,3-dichloro-4-propylphenyl)glycidamide, 3-ethyl-2-(2-chloro-3,4-difluorophenyl)glycidamide, 2-(2-bromo-4-ethylphenyl)glycidamide,

2-( 2-chloro-3-methylphenyl)glycidamide,

2-( 2,3-dichloro-4-fiuorophenyl)glycidamide,

3-chloro-3-bromo-2-(2-chloro-4-propylphenyl)glycidamide,

2-(2-chlorophenyl)glycidamide,

3-methyl-2-( 2-chloro-3-methylphenyl)glycidamide,

3 -chloro-2-(2-chloro-3,4-dimethylphenyl)glycidamide,

2-(2-chloro-4trifluoromethylphenyl)glycidamide,

3-chloro-2-(2-chloro-3-trifluoromethylphenyl)glycidamide and the like;

. when R is chlorine or bromine;

chlorine, bromine, hydrogen or alkyl of l-4 carbon 6 2'-(4-chlorophenyl)glycidamide, 2-(3,4-dichlorophenyl)glycidamide, 3-chloro-2-(4-bromophenyl)glycidamide, 3,3-dichloro-2-(2-methyl-4-chlorophenyl)glycidamide,. 3-ethyl2-(2-methyl-3,4-dichlorophenyl)glycidamide, 3-bromo-2-(3,4-dichlorophenyl)glycidamide, 3-chloro-2 -(2-butyl-3,4-dichlorophenyl)glycidamide, 3-chloro-2-(2-fluoro-4-bromophenyl)glycidamide, 3-chloro-2 -(2,3-difluoro-4-chlorophenyl)glycidamide, 3-chloro-,2-(2,3-dimethyl-4-chlorophenyl)glycidamide, 3-chloro-2-( 3-ethyl-4-bromophenyl)glycidamide, 3-bromo-2-( 2-fluoro-3-methyl-4-chlorophenyl)glycidamide, 2-( 2-trifluoromethyl-4-chlorophenyl)glycidamide, 3-chloro-2-(3-trifluoromethyl-4-chlorophenyl)glycidamide and the like; and when R; and R are chlorine or bromine;

2-(2,4 -dichlorophenyl)glycidamide, 2-(2,3,4-trichlorophenyl)glycidamide, 2-(3-methyl-2,4-dichlorophenyl)glycidamide, 3-chloro-2-(2,4-dibromophenyl)glycidamide, 3-chloro-2-(3-fluor0-2,4-dichlorophenyl)glycidamide, 3,3-dichloro-2-(2,3,4-trichlorophenyl)glycidamide, 3-methyl-2-(2,4-dichlorophenyl)glycidamide, 3-butyl-2-( 3methyl-2,4-dichlorophenyl)glycidamide, 2-(2,4-dichloro-3-trifluoromethylphenyl)glycidamide, 3-chloro-(2,4-dichloro-3-trifluoromethylphenyl)glycidamide and the like.

Within the Z-phenylglycidamides of formula II, a particularly preferred subclass because of their activity as nervous system depressants, especially as sedatives, hypnotics and anticonvulsants, are those where R is hydrogen or chlorine, preferably hydrogen, R, is hydrogen, chlorine or bromine, preferably chlorine, R is chlorine or methyl, R is hydrogen or chlorine, preferably hydrogen, and R is hydrogen, chlorine, fluorine or methyl, with the proviso that at least one of R and R, is chlorine. This is the most preferred subclass of the compounds of the invention.

Preferred species are: 3-chloro-2-(2,4-dichlorophenyl)glycidamide 3-chloro-2-(2-chloro-4-fluorophenyl)glycidamide 3-chloro-2-(2-chlorophenyl)glycidamide 3-bromo-2-(2,4-dichlorophenyl)glycidamide 3-chloro-2-(2-methyl-4-chlorophenyl)glycidamide 3-chloro-2-(2-chloro-4-methylphenyl)glycidamide 2-(2,4-dichlorophenyl)glycidamide 3 ,3 -dichloro-2-( 2 ,4-dichlorophenyl )glycidamide When the compounds of the invention contain different atoms substituted at the 3-position, i.e., X and Y are different, two stereoisomers can exist. It is to be understood that these isomers as well as mixtures of the two are within the scope of this invention.

The 2-phenylglycidamides of the invention find utility in the polymer field. For example, they are especially advantageous as modifiers of epoxy resins, particularly the glycidyl polyether resins such as are described and claimed in U.S. Pat. No. 2,633,458 with which they can be mixed in proportions of about 1:10 to 1:1 and cured in the usual way to obtain products of controlled properties, especially as regards flexibility. Those 2-phenylglycidamides containing halogen have the additional advantage of acting as fire-retardants when mixed with such epoxy resins and cured.

The most preferred subclass, as previously described,

I are particularly valuable as nervous system depressants, especially as hypnotics, sedatives and anticonvulsants.

PREPARATION The 2-phenylglycidamides of this invention, except for those of formula I in which Y is alkyl of l-4 carbon atoms, may be prepared by reaction of the appropriate a-(halomethyl)mandelamide with sodium hydroxide, sodium methoxideor sodium hydride. These (halomethyl)mandelamides, in turn, are readily prepared by the hydrolysis of the corresponding 0:- (halomethyl)mandelonitriles with 80-95 percent sulfuric acid at temperatures of from about 80-l10C, preferably about 95C. The a-(halomethyl)mandelonitriles are prepared by the known method of reacting the corresponding 2-haloacetophenones with hydrogen cyanide in the presence of a small amount of potassium cyanide as catalyst.

The 2-haloacetophenones may be prepared by a variety of methods. Most may be prepared by the well known Friedel-Crafts acylation of the appropriately substituted benzene with acetyl chloride or the appropriate monoor dihaloacetyl chloride. The 2-position of the appropriately ring-substituted acetophenone may be halogenated to form the 2,2- dihaloacetophenones using the appropriate halogen in formic acid. The 2,2,2-trihaloacetophenones may be prepared by the free-radical halogenation of the appropriate 2,2-dihaloacetophenone.

The 3-alkyl substituted 2-phenylglycidamide may be prepared by the alkaline peroxide oxidation of the appropriate B-alkylatroponitrile; these B-alkylatroponitriles, in turn, may be prepared by the base catalyzed condensation of the appropriate substituted benzylcyanide and aldehyde. These procedures are described more fully by Knowles et al., J. Am. Chem.

Soc., 54, 2028 (1932) and Vigier et al., Bull. Soc. Chim. France, 677 (1963).

As previously mentioned, those 2-phenylglycidamides substituted by two different atoms at the 3-position are capable of existing in two geometrically isomeric forms. For purposes of this invention those isomeric pairs that were separated have been designated as either a or [3. The B isomers were those that were the major component of the isomeric pair, generally were the lower melting, and had the longer chromatographic retention times on silica gel G. The a isomers conversely were the minor component of the isomeric pair and had shorter chromatographic retention times. The a isomers also tended to be more unstable relative to the B isomer of the pair. The stereochemical configurations of the a and ,B isomers were not determined.

The following examples are illustrative of the methods used to prepare the compounds of this invention. In those examples, parts means parts by weight unless otherwise expressly indicated, and parts by weight bear the same relationship to parts by volume as does the kilogram to the liter. All elemental analyses are based on percent by weight.

EXAMPLE 1.

Preparation of haloacetophenones a. 2,2,2,4,5'-Pentachloroacetophenone To a stirred slurry of 176 parts aluminum chloride in 218 parts 1,2,4-trichlorobenzene at 60C was added dropwise over 15 minutes 176 parts dichloroacetyl chloride. The reaction mixture was stirred at -90C for 4 hrs., cooled and poured into 2,000 parts by volumes of ice containing parts by volume concen-' trated hydrochloric acid. The aqueous mixture was extracted with ether. The combined extracts were washed with 1N hydrochloric acid, 5 percent aqueous sodium bicarbonate, saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. Stripping of the solvent afforded 309 parts crude brown liquid which upon distillation gave 264 parts (76 per cent) light yellow, 2,2,2',4',5'-pentachloroacetophenone, b.p. l17-l23C at 0.7 mm. The product was identified by infrared spectral analysis.

Cl Anal. Calc'd for C,H,CI,,O: 60.7 Found: 61.3

b. 2,2,2-Trichloroacetophenone Chlorine gas was bubbled into a stirred solution of 68 parts 2'-chloroacetophenone in 240 parts by volume glacial formic acid at 30C containing a small amount of dissolved hydrogen chloride. The reaction was continued for 4 hours while the temperature slowly rose to 50C. After standing overnight the reaction mixture was poured into water and the product was extracted with methylene chloride. The extracts were washed with 5 percent sodium bicarbonate solution and water, and dried with anhydrous magnesium sulfate. Solvent removal afforded 96 parts (98 percent) of slightly yellow liquid, 2,2,2'-trichloroacetophenone. The product was identified by infrared spectral analysis. c. 2 ,2 ,2 ,2 ,4 Pentachloroacetophenone Chlorine gas was slowly added over 30 hrs. with stirring to 307 parts 2,2,2,4'-tetrachloroacetophenone undergoing ultraviolet irradiation. The reaction temperature was maintained at l55160C. The product was stripped under high vacuum to give 347 parts (100 percent) of the yellow liquid, 2,2,2,2',4'pentachloroacetophenone. The product was identified by infrared spectral analysis.

Anal. Calcd for C H ChO: Found:

EXAMPLE 2 3-Chloro-2-(2,4-dichlorophenyl)glycidamide (a and B isomers) v reaction occurred causing reflux of the hydrogen cyanide. After. minutes refluxing, 100 parts by volume of etherand 4 parts by volume of concentrated sulfuric acid were added. The ether and excess hydrogen cyanide were removed by distillation and the resultant solid was recrystallized from hexane:benzene (19:1) to give 187 parts of 2,4-dichloro-ot-(dichloromethyl)mandelonitrile as a white 8 solid melting at 93-95C, identified by elemental analysis.

N Cl Anal. Calcd for NOCLC H 4.9 49.8 Found: 5.2 50.0

b. The nitrile from (a) above (300 parts) in 1,000 parts by volume of 80 percent sulfuric acid was heated on a steam bath for 16 hours, cooled and poured over ice. The resultant gummy precipitate was dissolved in methylene chloride, dried and cooled to give 258 parts of 2,4-dichloro-a-(dichloromethyl)mandelamide meltin g at l35-l37C. This was identified by infrared spectral analysis.

c. To a stirred suspension of 2.4parts of hexanewashed 50 percent sodium hydride-mineral oil suspension in 50 parts by volume'anhydrous tetrahydrofuran was added all at once a solution of 15 parts of the amide from (b) above .in v100 parts by volume of anhydrous tetrahydrofuran. An exothermic reaction occurred with hydrogen evolution and the formation of a white precipitate. The reaction mixture was stirred for 6 hours, poured into water, and extracted with ether. The ether extracts were washed with water, dried with anhydrous magnesium sulfate and the solvent was removed to afford a yellow viscous liquid. Recrystallization from'methylene chloride/hexane gave 6 parts white crystals, m.p. l l5 l2lC, containing a mixture of two isomers in a 6:1 ratio. Chromatographic separationof the mixture followed by recrystallization gave 3.1 parts of the B isomer (melting at l22-l23C) and 0.4 parts of the a isomer (melting at l70-l7l.5C) of 3-chloro-2-(2,4-dichlorophenyl)glycidamide which were identified by elemental and infrared spectral 5 analyses.

. N Cl Analysis Calcd for NO,Cl;C,l-l,: 5.3 39.9 Found for isomer (3) mp. l22"-l23C 5.3 39.7 Found for Isomer (0:) mp. 170l71.5C 5.3 39.7

d. To a stirred solution of 60.6 parts of the amide .fram (b) above in 175 parts by volume of anhydrous methanol was added dropwise a solution of 10.8 parts of sodium methoxide in lOO parts by volume of an- 15 hydrous methanol. The resulting solution was stirred at room temperature for 6 hours and allowed to stand overnight. The reaction mixture was poured into water and extracted with methylene chloride. The extracts were washed with water, dried with anhydrous magnesium sulfate and the solvent removed to afford a crude mixture of the two isomers as in method (c) above, which then chromatographed and recrystallized gave 34.3 parts of the B isomer, melting at l22l 24C and 1.7 parts of the a isomer melting at l69.5-l70C,

25 which were identified by Nuclear Magnetic Resonance and infrared spectral analyses.

EXAMPLE 3 2-(2,4-Dichlorophenyl)-3-propylglycidamide a. 2,4-Dichloro B-propylatroponitrile To a stirred mixture of 37.2 parts 2,4-dichlorobenzyl cyanide and 29 parts butyraldehyde was added with cooling a methanolic potassium hydroxide solution prepared from 0.l part potassium hydroxide and 50 parts by volume methanol. The reaction was heated to 60C for lhour, during which an additional 36 parts butyraldehyde was added. The mixture stood at room temperature for 246 days. Addition of 85 percent 40 phosphoric acid until acidic, stripping of the solvent and vacuum distillation afforded 17 parts (35 percent) of liquid 2,4-dichloro-B-propylatroponitrile, b.p. l25l28C at 0.05 mm.

N Cl Anal. Calcd for C l-l Cl Nz 5.8 29.6 Found: 56 28.5

b. A stirred mixture of 6.0 parts of the nitrile of (a) above, 5 parts by volume 30 percent hydrogen peroxide, 10 parts by volume sodium carbonate solution and minutes. Cooling, filtration of the resultant white crystals and recrystallization from ethanol gave 3.5 parts of 2-(2,4-dichlorophenyl)-3-propylglycidamide, m.p. 161-1 62C. The original filtrate afforded an additional 2.5 parts 2-(2,4-dichlorophenyl)-3-propylglycidamide, m.p. l60-l6lC from a hexane-benzene mixture. The total yield was 6.0 parts (88 percent).

Using the procedures of Examples l--3 the following 2-phenylglycidamides were prepared. The resultsare summarized in Table l. The compounds are identified by the following formula:

30 parts by volume acetone were heated at 52C for 30 l Z tlNll Y 'l;\ IKLI. I

IUllllti I Tso- Hal. 11a]. Compound Z X Y mer M.P., C. N Cl Br Eq. S C H N Cl Br Iaq. S C H A 2-Cl H Cl 101-104 6- 30. 5. 8 31. 0 5 2-C1 H C1 t 165-168. 5 6. 0 30. 5 5. 8 31. 0 4-C1 H Cl [3 90. 5-94 6. 0 30. 5 5. 9 31. 8 4-C1 H Cl 11 112. 5-113 6.0 30. 5 5. 0 31. 8 4-Br H Cl {3 108-109. 5 5.1 12. 8 4. 8 14. 5 4-Br H G1 a 102. 5-104 5. 1 12. 8 4. 7 13. 0 4-F H CI 5 113-117 6. 5 16. 5 6. 9 16.8 4-CH3 11 Cl 5 157-158. 5 6. 6 16. 8 7. 3 ll). 0 4-011. H 01 6.6 16.8 5.6 11). n 4-CH3SO2 H Cl I? 156-158. 5 5.1 12. ll 5. O 13. 5 2,5-C1 II Cl 5 160-162 5. 3 30.!) 5.4 40. 1 2,5-C1 11 C1 or 175. 5-177 5. 3 39. 9 2 40. 6 2,4-F H Cl fl 98-9!) 6. 0 15. 2 b. 0 14. J 2,3,4-C1 11 Cl {3 141. 5-143 4. 7 47 2 4. 5 47. 5 2,3,4-01 II Cl (1 192 4. 7 47 4. 6 42. 0 2,4,5-01 11 Cl 5 131. 6-135 4. 6 47 4.. 4 4. .5 2,4,5-Cl 1[ Cl 0: 162.5-166 4.0 47 l. 18.] .Z-(l l-l ll Cl {3 06-102 5. 6 28 .2 .2-( l, l-l II (l a 168-170 5. (i ...i -l 2,543! I] Hill. 5 *l'Jll (l. 0 30.11 .l 13,4 1 H 121 [27 ii. (I 30. (i .5 2,-1-(1 ll 13H Hurt tr. 22.x '15.; um .u 3b.:t um 15,44 3! ll lit-I'll: .l/l-l l ll Nil-Hi2 3 N()- ll l(l!l.5-l12.5 (.1 106-106. 5 11 06. 0-01). 0 II 112. 5-114. 5 11 98. 5-100. 5 11 140. 0-141.5

1 a and mixture. 2 Crude mixture.

NERVOUS SYSTEM DEPRESSANT ACTI\ 'ITY The hypnotic activity of these glycidamides was noted as follows. Mice were orally intubated with 500 mg/kg*(*mg/kg in these tests refers to milligrams of test compound per kilogram of animal body weight) of the test compound and observed at 15 minutes, 1 hour, 2 hours, 4 hours and 24 hours. Pharmacotoxic signs, especially onset and termination of the loss of righting reflex, were noted. Any compound inducing a loss in the righting reflex in 50 percent of the mice at any of these test intervals was considered active and were tested at lower oral doses and/or by intraperitoneal injection. Two reference drugs, Glutethimide and sodium pentobarbital, were included in the tests as controls. The results of the tests are shown in Table II.

l. 23 refers to beta isomer prepared in Example 2; other numbers refer to compounds ofTable l.

2. l-2 mice,-H-= 3-6 mice,+-H-= 7-9 mice and -H-H'= 10 mice out of 10 exhibited hypnotic activity.

3. at lOO mg/kg, not tested at [80 mg/kg.

4. All mice died.

5. 9 out of a total of 9 mice tested exhibited hypnotic response.

6. 2 out of a total of 5 mice tested exhibited hypnotic response.

7. Based on mean response of l 1 groups of 10 animals.

In addition to the hypnotic activity, compound 28 was also shown to exhibit other nervous system depressant effects. These include minor tranquilizing activity as shown by the pernicious preening test of Wilfon, J.

)G. et al., Fed. Proc., 19, 20 (1960); skeletal muscle relaxant activity as shown by antagonism to the lethal effect of intravenous injection of styrchnine sulfate; and, lastly, antagonism of supra-maximal electroshock seizure test of Swinyard, E. A., J. Am. Pharm. Assoc. 38, 201 (1949). The results of these tests are shown in Table III in comparison with the reference compounds, Glutethimide and sodium pentobarbital. The data show that compound 28 is more active and also has a greater safety factor (i.e. the ratio of LD zED is larger) than the two reference compounds.

Compositions according to the present invention also comprise a pharmaceutical carrier which may either be solid material or a liquid. Preparations for oral administration can be liquids or solids or any combination of these forms, such as syrups, elixirs, powders, capsules, or tablets. Preparations for administration of the active agent in unit dose form can be powders, compressed tablets, or a powder enclosed in a suitable capsule of absorbable material such as gelatin. The powders or compressed tablets may also comprise suitable excipients and/or diluents such as starch, lactose, stearic acid, magnesium stearate, dextrin or polyvinylpyrrolidone.

Preparations for parenteral administration may be sterile solutions or suspensions in liquids such as water, physiological saline, polyethylene glycol, mineral oil, ethyl oleate, methylcellulose, dimethyl sulfoxide or other liquid excipients known in the pharmaceutical and veterinary formulations art.

The unit dosage or therapeutically effective quantity of the glycidamides used according to this invention as analgesics, muscle relaxants, anticonvulsants and/or tranquilizers canvary over wide limits. For oral or parenteral administration in some cases, as little milligrams of the active material per kilogram of body weight can be effective in the reduction of pain or in effecting sedation and muscle relaxation, while seldom will a dosage in excess of about 200 milligrams per kilogram of body weight be required. In general, for oral administration the effective dosage will be from about to 200 milligrams per kilogram of body weight, while for parenteral .administration, the, effective dosage will be from about 10 to about 100 milligrams per kilograms of body weight. The hypnotic dose for the oral route is about 40 milligrams per kilogram of mammal body weight and the hypnotic dose for the parenteral route is 40 milligram per kilogram of mammal body weight. Each dosage unit form each capsule, tablet, ampoule, or prescribed dose can contain from about 1 percent to about 95 percent of active material, based upon the total weight of theformulation and preferably contains from about 2.5 percent to about 50 percent of the active material, on the same basis. Of course, it is possible to administer the therapeutics without the use of a pharmaceutical carri- The therapeutic agents used according to the invention can be administered either prior to or after the onset of the condition to be treated, such as wen they are used as: analgesics for the amelioration of pain; 3

motor depressants or tranquilizers to relieve nervous tension; central depressants to reduce hyperexcitability and induce sedation or as muscle relaxants for relief from pain and discomfort of disorders involving muscle wherein X is hydrogen or halogen, Y is hydrogen, halogen or alkyl of l-4 carbon atoms, Z is halogen, 3- nitro, alkyl of l-4 carbon atoms, trifluoromethyl or 4- alkylsulfonyl of l4 carbon atoms, H is hydrogen and n is a whole number from one to three; with the provisos that when n is less than 3, each Z may be the same or different, and when Y is alkyl, X is hydrogen.

2. A method of inducing an anticonvulsant response in mammals comprising administering to a mammal in need of such treatment an effective dosage for inducing an anticonvulsant response of a compound of the formula V o R Rl -i C l b 1 12 1 R1 NHz wherein R is chlorine, bromine or hydrogen, R is chlorine, bromine, hydrogen or alkyl of l-4 carbon atoms, and R R and R.,, which may bet the same or 0 different, are fluorine, chlorine, bromine, hydrogen,

trifluoromethyl or alkyl or l-4 carbon atoms; with the provisos that at least one of R and R4 is chlorine or bromine and that when R is alkyl, R is hydrogen.

3. The method according to claim 2 wherein R is spasms. hydrogen or chlorine, R is hydrogen, chlorine or TABLE m T Minor tranquilizing Antlstrychninc actlvlty Maximal clcctro-shock activity i.p. i.p.,mg./kg. 1.1)., lug/kg. I p Emu no EDS.) Lin Test compound (mg./kg.) LD ulED (mg/kg.) LDsu/EDso (mg/kg.) LDsu/EDm rug/kg,

Pentobarbital-N 2. 3

' mula bromine, R is chlorine or methyl, R is hydrogen or chlorine, and R is hydrogen, chlorine, fluorine or methyl; with the proviso that at least one of R and R is chlorine.

4. The method according to claim 3 wherein R, R

and R are hydrogen and R, and R are chlorine. 

2. A method of inducing an anticonvulsant response in mammals comprising administering to a mammal in need of such treatment an effective dosage for inducing an anticonvulsant response of a compound of the formula
 3. The method according to claim 2 wherein R is hydrogen or chlorine, R1 is hydrogen, chlorine or bromine, R2 is chlorine or methyl, R3 is hydrogen or chlorine, and R4 is hydrogen, chlorine, fluorine or methyl; with the proviso that at least one of R2 and R4 is chlorine.
 4. The method according to claim 3 wherein R, R1 and R3 are hydrogen and R2 and R4 are chlorine. 